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Microrna-365 Promotes Lung Carcinogenesis by Downregulating the USP33/SLIT2/ROBO1 Signalling Pathway

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Microrna-365 Promotes Lung Carcinogenesis by Downregulating the USP33/SLIT2/ROBO1 Signalling Pathway Wang et al. Cancer Cell Int (2018) 18:64 https://doi.org/10.1186/s12935-018-0563-6 Cancer Cell International PRIMARY RESEARCH Open Access MicroRNA‑365 promotes lung carcinogenesis by downregulating the USP33/ SLIT2/ROBO1 signalling pathway Yuhuan Wang1, Shuhua Zhang1, Hejing Bao2, Shukun Mu1, Baishen Zhang1, Hao Ma3 and Shudong Ma1* Abstract Background: Abnormal microRNA expression is closely related to cancer occurrence and development. miR-365a-3p plays an oncogenic role in skin cancer, but its role in lung cancer remains unclear. In this study, we aimed to investi- gate its role and underlying molecular mechanisms in lung cancer. Methods: Western blot and real-time quantitative PCR (qPCR) were used to detect the expression of miR-365a-3p in lung adenocarcinoma and lung cancer cell lines. The efects of miR-365a-3p on lung cancer cell proliferation, migra- tion, and invasion were also explored in vitro. The potential miR-365a-3p that targets USP33 was determined by dual luciferase reporter assay and verifed by qPCR and western blot analysis. miR-365a-3p acts as an oncogene by promot- ing lung carcinogenesis via the downregulation of the miR-365a/USP33/SLIT2/ROBO1 axis based on western blot analysis. Subcutaneous tumourigenesis further demonstrated that miR-365a-3p promotes tumour formation in vivo. Results: miR-365a-3p was upregulated in lung adenocarcinoma and lung cancer cell lines. Overexpression of miR- 365a-3p promoted and inhibition of miR-365a-3p suppressed the proliferation, migration, and invasion of lung cancer cells. We identifed USP33 as the downstream target of miR-365a-3p and observed a negative correlation between miR-365a-3p and USP33 expression in lung adenocarcinoma patients. The miR-365/USP33/SLIT2/ROBO1 axis, a new mechanism, was reported to inhibit the invasion and metastasis of lung cancer. A nude mouse model of lung cancer further verifed these fndings. Conclusions: In summary, miR-365a-3p acts as an oncogene by promoting lung carcinogenesis via the downregula- tion of the USP33/SLIT2/ROBO1 signalling pathway, making the miR-365/USP33/SLIT2/ROBO1 axis a new mechanism of lung cancer promotion and a novel therapeutic target for predicting prognosis and response to gene therapy. Keywords: Adenocarcinoma of lung, Carcinogenesis, Deubiquitinating enzymes, MicroRNAs, Oncogenes Background medicine [3–5]. Terefore, identifying genes that drive According to the World Health Organization (WHO), cancer progression and providing efective treatments cancer is the leading cause of death worldwide, and lung may signifcantly prolong the survival of patients with cancer is the main cause of cancer-related deaths [1]. In non-small cell lung cancer (NSCLC) [6, 7]. 2017, there were an estimated 222,500 new diagnoses of MicroRNAs (miRNAs) are small, highly conserved, lung cancer in the United States, and 155,870 people died noncoding RNAs of approximately 19–25 nucleotides of lung cancer [2]. With advances in medical technology, that regulate gene expression at the post-transcriptional lung cancer treatment has entered the era of precision level by base-pairing with the 3′ UTRs of target mRNAs [8–11]. Tey play key roles in human biological processes, such as migration, cellular metabolism, cell proliferation, *Correspondence: [email protected] 1 Department of Oncology, Nanfang Hospital, Southern Medical apoptosis, and epithelial–mesenchymal transition (EMT) University, Guangzhou 510515, Guangdong, China [12–17]. Increasing evidence has demonstrated that miR- Full list of author information is available at the end of the article NAs play an important role in cancer and are closely © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat​iveco​mmons​.org/licen​ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat​iveco​mmons​.org/ publi​cdoma​in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Wang et al. Cancer Cell Int (2018) 18:64 Page 2 of 14 related to tumourigenesis and prognosis. Te miRNA signalling participates in the development of cancer [29, miR-365 gene is located on chromosome 16p13.12, and 30]. Tus, in this study, we aimed to elucidate the role the mature hsa-miR-365 sequence is cleaved from two of miR-365a-3p in lung cancer cells and the relationship precursors: hsa-miR-365-1 and hsa-miR-365-2 [18]. among miR-365a-3p, USP33, SLIT2, and ROBO1 in lung Abnormal expression of miR-365 is observed in a variety adenocarcinoma. of tumours, with diferent expression patterns and func- tions in diferent human cancer types. In skin squamous Methods cell carcinoma, we frst found that miR-365a-3p plays Tissue samples an oncogenic role by downregulating NFIB to promote Tis study was approved by the Ethics Review Board of CDK6 and CDK4 expression, leading to Rb phospho- Nanfang Hospital, Southern Medical University (Guang- rylation and tumour progression [18–20]. Additionally, zhou, China). Twenty pairs of primary lung cancer tis- high expression levels of miR-365a-3p can be detected in sues and their corresponding adjacent non-tumour tissue breast and pancreatic cancer, playing a role in promot- samples were collected in the Toracic Surgery Depart- ing tumour development [21, 22]. In colon cancer, miR- ment of Nanfang Hospital from March to June 2017. 365a-3p inhibits the development of cancer by targeting All experiments were performed according to relevant cyclin D1 and BCL-2 [23, 24]. Tis miRNA also serves guidelines; informed consent was obtained from each as a tumour suppressor gene in gastric cancer [25]. In patient. No patients received prior radiotherapy or chem- brief, the functions of miR-365a-3p in cancer are com- otherapy. All specimens were removed during surgery plex. Tus, the roles of miR-365a-3p in lung cancer cells and immediately stored at − 80 °C in liquid nitrogen for remain unclear and require further study. subsequent extraction of total RNA. Deubiquitinating enzymes are key enzymes that can reverse ubiquitination modifcations. Recently, their Cell lines and cell culture functions and mechanisms have been of great interest in A549 cells were purchased from the American Type Cul- tumour research [26, 27]. USP33, also known as VHL- ture Collection (ATCC, Manassas, VA, USA). SPC-A-1 interacting deubiquitinating enzyme 1 (VDU1), is located and H1299 cells were purchased from the Shanghai Cell on chromosome 1 and encodes two protein subtypes: Bank of the Chinese Academy of Sciences (Shanghai, type I and type II. Type I contains 942 amino acids, and China). All cells were cultured in RPMI-1640 medium or type II contains 911 amino acids, with predicted molecu- DMEM supplemented with 10% FBS (Gibco, Gaithers- lar weights of 107 and 103 kDa, respectively. USP33 has burg, MD, USA). All cells were maintained in a humidi- been confrmed to inhibit the development of a variety of fed incubator at 37 °C and 5% CO2. tumour cells. USP33 deubiquitinates and thus maintains the stability of ROBO1, thereby regulating the activity RNA extraction and real‑time quantitative RT‑PCR of SLIT2 and inhibiting cancer cell metastasis [28–30]. (qRT‑PCR) USP33 maintains the stability of CP110 and antagonises Total RNA was extracted from cell lines or tissues using the efect of cyclin-F on the S/G2 and G2/M phases of a TRIzol Kit (Takara Bio, Shiga, Japan) according to the the cell cycle by interacting with CP110, maintaining the manufacturer’s instructions. cDNA was synthesized using steady state of the centriole and ensuring normal func- Takara RT reagent (Takara Bio). qRT-PCR was performed tioning of mitosis and genome stability, which reduces on a Light Cycler 480 system (Roche Diagnostics, Basel, tumourigenesis [31]. Switzerland) using a SYBR Green I Master kit (Roche). Additionally, SLIT2/ROBO1 signalling has been shown We used glyceraldehyde-3-phosphate dehydrogenase to inhibit tumour cell proliferation and migration. Prasad (GAPDH) as an internal reference. Mature miR-365a-3p et al. [32] found that ROBO1 and ROBO2 were expressed expression was measured by qRT-PCR according to the in several breast cancer cell lines and that SLIT2 inhib- Taqman MicroRNA Assay protocol (Takara Bio) and ited CXCL12/CXCR4-induced chemotaxis, invasion, normalised using U6 small nuclear RNA with the 2 −ΔΔCt adhesion, and secretion of MMP-2 and MMP-9 in breast method. cancer cells. Te loss of SLIT2, SLIT3, or ROBO1 protein in mouse breast cancer models results in an increase in Western blotting repair processes in tissues, promoting cell proliferation Equal amounts of protein were separated by 10% SDS- [33]. PAGE and blotted onto PVDF membranes (Millipore, Our previous studies showed that in cutaneous squa- Bedford, MA, USA) probed with the following primary mous cell carcinoma, miR-365a-3p plays an oncogenic and secondary antibodies: monoclonal rabbit primary role by promoting tumour progression [18]. Moreover, antibodies against SLIT2 and ROBLO1 (1:1000; Cell studies have shown that USP33-mediated SLIT2/ROBO1 Signaling Technology, Boston, MA, USA) and β-tubulin Wang et al. Cancer Cell Int (2018) 18:64 Page 3 of 14 (1:10,000; Bioworld Technology Inc., St. Louis Park, MN, precoated with Matrigel. Each assay was performed at USA); polyclonal rabbit primary antibody against USP33 least three times independently. (1:500; Abcam, San Francisco, CA, USA); and secondary fuorescent goat anti-rabbit antibody (LI-COR, Lincoln, Wound healing assay NE, USA). Primary antibodies were applied overnight at When cells had grown to approximately 90% confuency 4 °C, and secondary antibody treatment was performed (after 48 h), an artifcial wound was created with a 10-µL for about 1 h at 25 °C.
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